TNF (Tumor necrosis factor) variants and mutations
TNF (also known as Tumor necrosis factor) is a human protein-coding gene encoding a tumor necrosis factor protein. It coordinates inflammation, fever, immune-cell activation, and cell survival or death through TNF receptors. Excessive TNF signaling is central to diseases such as rheumatoid arthritis and inflammatory bowel disease, making TNF blockade one of the most successful anti-inflammatory treatment strategies. This analysis covers 449 TNF variants and mutations. Of these, 92% have computational variant effect predictions. Disease context includes psoriatic arthritis, psoriasis, and rheumatoid arthritis. Example TNF variants include S2N, S2R, and T3A.
Variant analysis overview
- Gene: TNF
- Protein: Tumor necrosis factor
- UniProt accession: P01375
- Organism: Homo sapiens
- Variants analyzed: 449
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 208 unspecified-consequence records; 112 missense variants; 112 synonymous variants; 7 frameshift variants; 2 in-frame deletions; 3 stop-gained variants; 1 in-frame insertions; 4 substitution
- Prediction scores: 413 variants have prediction scores (92% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: psoriatic arthritis, psoriasis, rheumatoid arthritis, ulcerative colitis, juvenile idiopathic arthritis, ankylosing spondylitis, Crohn disease, psoriasis vulgaris, uveitis, hidradenitis suppurativa, immune system disorder, pustular psoriasis.
Protein structure and variant hotspots
- Protein features: 1 transmembrane segments; 1 domains; 2 post-translational modification sites.
- Structural context: 298 variants have structural context.
- PTM context: 3 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable TNF variants
Examples include S2N, S2R, T3A, T3P, T3T, E4G, E4Q, S5N. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- S2N (p.Ser2Asn), 1000Genomes rs2150388436, REVEL 0.41, CADD 26.70
- S2R (p.Ser2Arg), gnomAD 6-31575747-C-A, REVEL 0.45, CADD 25.90
- T3A (p.Thr3Ala), gnomAD rs1771144082, REVEL 0.45, CADD 25.50
- T3P (p.Thr3Pro), gnomAD rs1771144082
- T3T (p.Thr3Thr), gnomAD 6-31575750-T-C, CADD 4.91
- E4G (p.Glu4Gly), gnomAD rs1445719601, REVEL 0.43, CADD 28.60
- E4Q (p.Glu4Gln), Ensembl rs953747858, REVEL 0.40, CADD 25.50
- S5N (p.Ser5Asn), ExAC rs771650207, gnomAD rs771650207, REVEL 0.17, CADD 17.70
- S5R (p.Ser5Arg), ExAC rs747694851, TOPMed rs747694851, gnomAD rs747694851, REVEL 0.37, CADD 26.40
- S5A (p.Ser5Ala), gnomAD 6-31575751-GA-G, CADD 27.80
- S5S (p.Ser5Ser), rs565862537, gnomAD 6-31575756-C-T, CADD 14.60
- M6K (p.Met6Lys), rs2150388461, Ensembl rs2150388461, ClinGen CA363342812, ClinVar RCV002267699, REVEL 0.58, CADD 27.10, Uncertain significance, Migraine with or without aura, susceptibility to, 1
- M6V (p.Met6Val), gnomAD 6-31575757-A-G, REVEL 0.41, CADD 24.80
- M6I (p.Met6Ile), gnomAD 6-31575759-G-T, REVEL 0.45, CADD 26.00
- I7T (p.Ile7Thr), TOPMed rs1288613011, gnomAD rs1288613011, REVEL 0.43, CADD 27.60
- I7V (p.Ile7Val), gnomAD 6-31575760-A-G, REVEL 0.31, CADD 20.60
- I7F (p.Ile7Phe), gnomAD 6-31575760-A-T, REVEL 0.41, CADD 27.30
- I7N (p.Ile7Asn), gnomAD 6-31575761-T-A, REVEL 0.45, CADD 29.20
- R8P (p.Arg8Pro), 1000Genomes rs201502336, ExAC rs201502336, TOPMed rs201502336, gnomAD rs201502336, REVEL 0.46, CADD 23.70
- R8Q (p.Arg8Gln), 1000Genomes rs201502336, ExAC rs201502336, TOPMed rs201502336, gnomAD rs201502336, REVEL 0.17, CADD 21.80
- R8W (p.Arg8Trp), ESP rs374531985, ExAC rs374531985, TOPMed rs374531985, gnomAD rs374531985, REVEL 0.48, CADD 25.70
- R8R (p.Arg8Arg), gnomAD 6-31575763-C-A, CADD 14.80
- D9N (p.Asp9Asn), TOPMed rs982610810, gnomAD rs982610810, REVEL 0.52, CADD 29.50
- D9D (p.Asp9Asp), rs377627218, gnomAD 6-31575768-C-T, CADD 7.38
- D9E (p.Asp9Glu), gnomAD 6-31575768-C-A, REVEL 0.46, CADD 18.80
- V10L (p.Val10Leu), ExAC rs759696973, TOPMed rs759696973, gnomAD rs759696973, SIFT 0.11
- V10M (p.Val10Met), rs759696973, ExAC rs759696973, TOPMed rs759696973, gnomAD rs759696973, REVEL 0.41, CADD 26.50, Variant assessed as somatic; moderate impact.
- V10V (p.Val10Val), rs770023902, gnomAD 6-31575771-G-A, CADD 13.40
- L12M (p.Leu12Met), gnomAD 6-31575775-C-A, REVEL 0.36, CADD 23.00
- L12L (p.Leu12Leu), gnomAD 6-31575777-G-A, CADD 11.00
- A13D (p.Ala13Asp), gnomAD 6-31575779-C-A, REVEL 0.52, CADD 24.20
- A13V (p.Ala13Val), gnomAD 6-31575779-C-T, REVEL 0.42, CADD 24.20
- A13A (p.Ala13Ala), rs1471476571, gnomAD 6-31575780-C-A, CADD 1.10
- E14K (p.Glu14Lys), ExAC rs775506502, gnomAD rs775506502, REVEL 0.38, CADD 22.60
- E14E (p.Glu14Glu), rs1417263279, gnomAD 6-31575783-G-A, CADD 8.30
- E15K (p.Glu15Lys), Ensembl rs972459518, REVEL 0.34, CADD 24.00
- E15Q (p.Glu15Gln), gnomAD 6-31575784-G-C, REVEL 0.38, CADD 23.50
- A16G (p.Ala16Gly), ExAC rs763000109, gnomAD rs763000109, REVEL 0.23, CADD 9.90
- A16V (p.Ala16Val), ExAC rs763000109, gnomAD rs763000109, REVEL 0.12, CADD 1.00
- A16T (p.Ala16Thr), gnomAD 6-31575787-G-A, REVEL 0.19, CADD 10.80
- A16E (p.Ala16Glu), gnomAD 6-31575788-C-A, REVEL 0.13, CADD 1.64
- A16A (p.Ala16Ala), rs146375573, gnomAD 6-31575789-G-A, CADD 1.76
- L17V (p.Leu17Val), gnomAD rs1395544606, REVEL 0.29, CADD 13.90
- P18S (p.Pro18Ser), gnomAD rs1375111873, REVEL 0.09, CADD 6.50
- P18T (p.Pro18Thr), gnomAD 6-31575793-C-A, REVEL 0.16, CADD 5.97
- K19R (p.Lys19Arg), 1000Genomes rs377338702, ESP rs377338702, ExAC rs377338702, TOPMed rs377338702, REVEL 0.10, CADD 9.15
- K19T (p.Lys19Thr), 1000Genomes rs377338702, ESP rs377338702, ExAC rs377338702, TOPMed rs377338702, REVEL 0.22, CADD 17.70
- K19E (p.Lys19Glu), gnomAD 6-31575796-A-G, REVEL 0.13, CADD 19.70
- K19K (p.Lys19Lys), gnomAD 6-31575798-G-A, CADD 8.34
- K20E (p.Lys20Glu), gnomAD rs1326672610, REVEL 0.29, CADD 20.30
- K20R (p.Lys20Arg), TOPMed rs1771149240, SIFT 0.02
- K20K (p.Lys20Lys), gnomAD 6-31575801-G-A, CADD 7.59
- T21I (p.Thr21Ile), TOPMed rs1160009797, gnomAD rs1160009797, REVEL 0.10, CADD 17.20
- T21T (p.Thr21Thr), rs766034823, gnomAD 6-31575804-A-C, CADD 6.13
- G22E (p.Gly22Glu), TOPMed rs1405990400
- G22R (p.Gly22Arg), ExAC rs753713562, gnomAD rs753713562, REVEL 0.07, CADD 12.70
- G22W (p.Gly22Trp), gnomAD 6-31575805-G-T, REVEL 0.07, CADD 17.60
- G22G (p.Gly22Gly), gnomAD 6-31575807-G-C, CADD 9.46
- G23E (p.Gly23Glu), gnomAD rs1234547532, REVEL 0.25, CADD 23.10
- G23R (p.Gly23Arg), gnomAD rs1353047835, REVEL 0.29, CADD 25.50
- G23V (p.Gly23Val), gnomAD rs1234547532, REVEL 0.30, CADD 23.00
- G23G (p.Gly23Gly), gnomAD 6-31575810-G-T, CADD 8.25
- P24A (p.Pro24Ala), ExAC rs754639425, TOPMed rs754639425, gnomAD rs754639425, NCI-TCGA TCGA novel, REVEL 0.07, CADD 13.00, Variant assessed as somatic; high impact.
- P24S (p.Pro24Ser), ExAC rs754639425, TOPMed rs754639425, gnomAD rs754639425, REVEL 0.07, CADD 15.00
- P24T (p.Pro24Thr), ExAC rs754639425, TOPMed rs754639425, gnomAD rs754639425, REVEL 0.20, CADD 18.50
- P24L (p.Pro24Leu), gnomAD 6-31575812-C-T, REVEL 0.11, CADD 19.80
- Q25E (p.Gln25Glu), ExAC rs764955335, gnomAD rs764955335, REVEL 0.24, CADD 16.70
- Q25R (p.Gln25Arg), gnomAD 6-31575803-CA-C, CADD 17.80
- G26A (p.Gly26Ala), TOPMed rs1271411982, gnomAD rs1271411982, REVEL 0.23, CADD 20.20
- G26D (p.Gly26Asp), TOPMed rs1271411982, gnomAD rs1271411982, REVEL 0.23, CADD 16.90
- G26S (p.Gly26Ser), gnomAD 6-31575817-G-A, REVEL 0.16, CADD 18.40
- S27S (p.Ser27Ser), rs1439859972, gnomAD 6-31575822-C-T, CADD 11.70
- R28K (p.Arg28Lys), TOPMed rs1192279581, gnomAD rs1192279581, REVEL 0.09, CADD 12.60
- R28R (p.Arg28Arg), rs779870893, gnomAD 6-31575825-G-A, CADD 2.05
- R29L (p.Arg29Leu), NCI-TCGA TCGA novel, SIFT 0.02, Variant assessed as somatic; moderate impact.
- R29Q (p.Arg29Gln), 1000Genomes rs576621666, ExAC rs576621666, TOPMed rs576621666, gnomAD rs576621666, REVEL 0.41, CADD 22.70
- R29W (p.Arg29Trp), rs1260793650, gnomAD rs1260793650, NCI-TCGA Cosmic COSV1014, NCI-TCGA Cosmic COSV6930, REVEL 0.33, CADD 22.50, Variant assessed as somatic; moderate impact.
- R29R (p.Arg29Arg), gnomAD 6-31575826-C-A, CADD 6.22
- C30Y (p.Cys30Tyr), NCI-TCGA TCGA novel, SIFT 0.03, Variant assessed as somatic; moderate impact.
- L31S (p.Leu31Ser), gnomAD rs1771153168, REVEL 0.61, CADD 15.00
- F32S (p.Phe32Ser), ExAC rs777405140, gnomAD rs777405140
- L33F (p.Leu33Phe), ExAC rs747406665, TOPMed rs747406665, gnomAD rs747406665, REVEL 0.35, CADD 20.80
- S34R (p.Ser34Arg), TOPMed rs1418646618, gnomAD rs1418646618, REVEL 0.65, CADD 23.60
- S34T (p.Ser34Thr), TOPMed rs915225183, gnomAD rs915225183, REVEL 0.27, CADD 19.70
- L35F (p.Leu35Phe), gnomAD 6-31575844-C-T, REVEL 0.45, CADD 15.10
- S37del (p.Ser37del), rs1475246336, gnomAD 6-31575848-TCTC-T, CADD 18.50
- S37S (p.Ser37Ser), rs1301033055, gnomAD 6-31575852-C-T, CADD 11.90
- F38L (p.Phe38Leu), ExAC rs757794184, gnomAD rs757794184, REVEL 0.53, CADD 27.00
- F38F (p.Phe38Phe), gnomAD 6-31575855-C-T, CADD 12.20
- I40I (p.Ile40Ile), rs141667614, gnomAD 6-31575861-C-T, CADD 0.66
- V41L (p.Val41Leu), rs558678940, 1000Genomes rs558678940, ExAC rs558678940, TOPMed rs558678940, REVEL 0.12, CADD 12.90, Uncertain significance, not specified
- V41M (p.Val41Met), 1000Genomes rs558678940, ExAC rs558678940, TOPMed rs558678940, gnomAD rs558678940, REVEL 0.39, CADD 23.50, Uncertain significance
- V41A (p.Val41Ala), gnomAD 6-31575863-T-C, REVEL 0.42, CADD 24.00
- A42P (p.Ala42Pro), gnomAD rs1312232547, REVEL 0.64, CADD 24.40
- A42T (p.Ala42Thr), gnomAD 6-31575865-G-A, REVEL 0.55, CADD 23.10
- A42A (p.Ala42Ala), gnomAD 6-31575867-A-G, CADD 10.40
- G43G (p.Gly43Gly), rs369163834, gnomAD 6-31575870-C-G, CADD 3.24
- A44T (p.Ala44Thr), TOPMed rs867435711, gnomAD rs867435711, REVEL 0.43, CADD 25.30
- A44S (p.Ala44Ser), gnomAD 6-31575871-G-T, REVEL 0.42, CADD 23.20
- T45I (p.Thr45Ile), 1000Genomes rs948780599
- T45S (p.Thr45Ser), 1000Genomes rs948780599, REVEL 0.50, CADD 23.40
- T46M (p.Thr46Met), 1000Genomes rs200241887, ExAC rs200241887, TOPMed rs200241887, gnomAD rs200241887, REVEL 0.12, CADD 8.75
- T46K (p.Thr46Lys), gnomAD 6-31575878-C-A, REVEL 0.37, CADD 14.30
- T46T (p.Thr46Thr), rs144480538, gnomAD 6-31575879-G-A, CADD 0.39
- L47F (p.Leu47Phe), TOPMed rs1036935762
- L47I (p.Leu47Ile), gnomAD 6-31575880-C-A, REVEL 0.37, CADD 24.10
- L47L (p.Leu47Leu), rs541347219, gnomAD 6-31575882-C-T, CADD 9.27
- F48L (p.Phe48Leu), Ensembl rs2150388657
- C49S (p.Cys49Ser), gnomAD rs1771156812, REVEL 0.67, CADD 25.20
- C49* (p.Cys49Ter), gnomAD 6-31575888-C-A, CADD 33.00
- L50M (p.Leu50Met), gnomAD 6-31575889-C-A, REVEL 0.54, CADD 24.30
- L50L (p.Leu50Leu), gnomAD 6-31575889-C-T, CADD 12.30
- L51L (p.Leu51Leu), rs2150388663, gnomAD 6-31575892-C-T, CADD 13.20
- L51M (p.Leu51Met), gnomAD 6-31575892-C-A, REVEL 0.59, CADD 24.80
- H52N (p.His52Asn), TOPMed rs3179060, gnomAD rs3179060
- H52Q (p.His52Gln), Ensembl rs1562479959, REVEL 0.36, CADD 18.90
- H52Y (p.His52Tyr), TOPMed rs3179060, gnomAD rs3179060, REVEL 0.45, CADD 23.00
- F53S (p.Phe53Ser), NCI-TCGA Cosmic COSV1014, SIFT 0.00, Variant assessed as somatic; moderate impact.
- G54E (p.Gly54Glu), ExAC rs756182468, TOPMed rs756182468, gnomAD rs756182468, REVEL 0.29, CADD 22.10, Uncertain significance, Increased circulating interleukin 6 concentration
- G54G (p.Gly54Gly), gnomAD 6-31575903-A-G, CADD 9.64
- V55M (p.Val55Met), gnomAD 6-31575904-G-A, REVEL 0.41, CADD 27.00
- V55V (p.Val55Val), gnomAD 6-31575906-G-A, CADD 10.80
- I56I (p.Ile56Ile), gnomAD 6-31575909-C-A, CADD 12.60
- G57S (p.Gly57Ser), rs777874746, TOPMed rs777874746, gnomAD rs777874746, REVEL 0.56, CADD 29.50, Uncertain significance, not specified
- G57V (p.Gly57Val), gnomAD 6-31575911-G-T, REVEL 0.64, CADD 29.20
- G57D (p.Gly57Asp), gnomAD 6-31575911-G-A, REVEL 0.62, CADD 25.90
- G57G (p.Gly57Gly), gnomAD 6-31575912-C-A, CADD 12.70
- P58S (p.Pro58Ser), gnomAD 6-31575913-C-T, REVEL 0.55, CADD 26.50
- P58T (p.Pro58Thr), gnomAD 6-31575913-C-A, REVEL 0.55, CADD 26.00
- P58L (p.Pro58Leu), gnomAD 6-31575914-C-T, REVEL 0.58, CADD 25.20
- P58H (p.Pro58His), gnomAD 6-31575914-C-A, REVEL 0.56, CADD 27.20
- P58P (p.Pro58Pro), gnomAD 6-31575915-C-G, CADD 12.60
- Q59R (p.Gln59Arg), TOPMed rs1485010267, gnomAD rs1485010267, REVEL 0.42, CADD 26.40
- R60G (p.Arg60Gly), gnomAD rs1213638600, REVEL 0.15, CADD 18.60
- R60K (p.Arg60Lys), gnomAD 6-31575920-G-A, REVEL 0.07, CADD 10.80
- R60R (p.Arg60Arg), gnomAD 6-31575921-G-A, CADD 13.30
- R60S (p.Arg60Ser), gnomAD 6-31575921-G-C, REVEL 0.15, CADD 19.30
- E61K (p.Glu61Lys), gnomAD rs1258319339, REVEL 0.27, CADD 23.40
- E61Q (p.Glu61Gln), gnomAD rs1258319339, REVEL 0.28, CADD 24.30
- E61G (p.Glu61Gly), gnomAD 6-31575923-A-G, REVEL 0.26, CADD 23.40
- E61E (p.Glu61Glu), rs759378982, gnomAD 6-31575924-A-G, CADD 10.40
- E62D (p.Glu62Asp), NCI-TCGA TCGA novel, REVEL 0.35, CADD 32.00, Variant assessed as somatic; moderate impact.
- E62G (p.Glu62Gly), ExAC rs765178016, gnomAD rs765178016, REVEL 0.34, CADD 32.00
- P64L (p.Pro64Leu), ExAC rs35131721, TOPMed rs35131721, gnomAD rs35131721, REVEL 0.16, CADD 9.85
- P64S (p.Pro64Ser), gnomAD rs1250915035, REVEL 0.11, CADD 1.94
- P64P (p.Pro64Pro), rs772331441, gnomAD 6-31576539-C-T, CADD 1.07
- R65G (p.Arg65Gly), TOPMed rs1771189266
- R65S (p.Arg65Ser), NCI-TCGA Cosmic COSV6930, Variant assessed as somatic; moderate impact.
- D66N (p.Asp66Asn), ExAC rs776692566, TOPMed rs776692566, gnomAD rs776692566, REVEL 0.18, CADD 6.69, Uncertain significance, not specified
- L67F (p.Leu67Phe), gnomAD 6-31576546-C-T, REVEL 0.17, CADD 0.62
- L67V (p.Leu67Val), gnomAD 6-31576546-C-G, REVEL 0.19, CADD 0.75
- S68F (p.Ser68Phe), gnomAD 6-31576550-C-T, REVEL 0.17, CADD 0.53
- L69V (p.Leu69Val), ExAC rs759609722, TOPMed rs759609722, gnomAD rs759609722, REVEL 0.14, CADD 2.93
- L69L (p.Leu69Leu), rs759609722, gnomAD 6-31576552-C-T, CADD 2.58
- L69P (p.Leu69Pro), gnomAD 6-31576553-T-C, REVEL 0.17, CADD 9.53
- I70N (p.Ile70Asn), gnomAD 6-31576556-T-A, REVEL 0.13, CADD 7.61
- L73P (p.Leu73Pro), TOPMed rs956294956, REVEL 0.46, CADD 23.00
- L73L (p.Leu73Leu), rs1432589922, gnomAD 6-31576564-C-T, CADD 5.50
- A74D (p.Ala74Asp), Ensembl rs1771190390
- A74T (p.Ala74Thr), TOPMed rs972350853, gnomAD rs972350853, REVEL 0.16, CADD 16.00
- A74V (p.Ala74Val), NCI-TCGA Cosmic COSV1014, Variant assessed as somatic; moderate impact.
- p.Gln75 Ala76del, gnomAD 6-31576565-TGGCCC, CADD 16.40
- Q75E (p.Gln75Glu), gnomAD 6-31576570-C-G, REVEL 0.34, CADD 16.40
- Q75Q (p.Gln75Gln), rs769643681, gnomAD 6-31576572-G-A, CADD 6.48
- A76A (p.Ala76Ala), gnomAD 6-31576575-A-G, CADD 6.38
- V77=, NCI-TCGA Cosmic COSV6930, Variant assessed as somatic; low impact.
- V77I (p.Val77Ile), gnomAD 6-31576576-G-A, REVEL 0.13, CADD 14.90
- R78G (p.Arg78Gly), ExAC rs775365890, gnomAD rs775365890, REVEL 0.31, CADD 21.90
- R78K (p.Arg78Lys), Ensembl rs1771201159, REVEL 0.34, CADD 23.10
- R78S (p.Arg78Ser), gnomAD 6-31576768-A-T, REVEL 0.36, CADD 23.00
- S79* (p.Ser79Ter), gnomAD 6-31576770-C-A, CADD 37.00, SIFT 0.17
- S80P (p.Ser80Pro), ESP rs369783162, ExAC rs369783162, TOPMed rs369783162, gnomAD rs369783162, REVEL 0.41, CADD 23.50
- R82* (p.Arg82Ter), TOPMed rs1234953150
- R82P (p.Arg82Pro), ExAC rs772270241, TOPMed rs772270241, gnomAD rs772270241
- R82Q (p.Arg82Gln), rs772270241, ExAC rs772270241, TOPMed rs772270241, gnomAD rs772270241, REVEL 0.16, CADD 17.80, Variant assessed as somatic; moderate impact.
- T83N (p.Thr83Asn), TOPMed rs897338372, gnomAD rs897338372, REVEL 0.14, CADD 3.45, Uncertain significance, Inherited susceptibility to asthma; Migraine with or without aura, susceptibilit
- T83S (p.Thr83Ser), gnomAD 6-31576781-A-T, REVEL 0.21, CADD 7.13
- T83T (p.Thr83Thr), rs1771202205, gnomAD 6-31576783-C-T, CADD 6.74, SIFT 0.00
- T83A (p.Thr83Ala), rs972350853, []
- P84L (p.Pro84Leu), rs4645843, 1000Genomes rs4645843, ESP rs4645843, ExAC rs4645843, REVEL 0.19, CADD 14.30, Benign/Likely benign, not provided
Public TNF analysis runs
- TNF analysis run — TNF (449 variants) — completed 2026-08-19